Currently, medical castration using hormone drugs is widely used for cancer therapy, but there are cancers which do not respond to hormone drugs (hormone-independent cancer). Also in hormone-dependent cancers exhibiting effects in hormone therapy, it is known that when therapy is continued, hormone-dependent cancers change into hormone-independent cancers by proliferation of hormone-independent cancers (Laboratory Investigation 67, 540, 1992).
Therefore, in therapy for cancers (in particular, prostate cancer, breast cancer, etc.), it is ideal that drugs are properly used according to a type of cancer such as cancer which responds to hormone therapy and cancer which does not respond to hormone therapy, a stage of cancer disease, an age, etc. of an individual patient. However, a method of effectively treating hormone-independent cancers has not been heretofore known.
Apoptosis refers to, for example, cell shrinkage, chromatin condensation, nucleus concentration, disappearance of microvillus on the cell surface, plasma membrane blebbing, apoptotic body formation, gap between peripheral cells accompanied with cell shrinkage, and removal by phagocytes (Japan Clinic, vol. 54, No. 7 (1996)). Apoptosis or programmed cell death plays an important role in individual development and homeostasis maintenance in a living body. It has been gradually made clear that abnormality of apoptosis causes diseases such as cancers, autoimmune diseases and nervous diseases.
Benzimidazole derivatives having an AII antagonism are known as remedies for hypertension, cardiac diseases (hypercardia, heart failure, cardiac infarction etc.), cerebral apoplexy, and circulatory diseases such as nephritis (JP-A 4-364171, etc.), and it is known that persistent hypotension action is manifested by inhibiting action of AII having strong vasoconstriction activity on an AII receptor.
In addition, it has been reported that an angiotensin II receptor (AT1 receptor) is involved in development and proliferation of cancer cells. (FEBS Letters 495(2001), 197-200; British Journal of Cancer, 1997, 75(9), 1279-1283; The Journal of Urology, vol. 151, 208-213, 1994; Cancer Letters 110 (1996)19-27).
However, there is no report suggesting that compounds having an AII antagonism exhibit effects of treating or preventing hormone-independent cancers, effects of inhibiting hormone-independent cancer cell proliferation and effects of inducing apoptosis of cancer cells.
In addition, WO99/44590 and WO01/60410 disclose sustained-release preparations containing benzimidazole derivatives having an AII antagonism. However, there is no description that the sustained-release preparations have effects of treating or preventing hormone-independent cancers, effects of inhibiting hormone-independent cancer cell proliferation, effects of inducing apoptosis of cancer cells and effects of treating or preventing cancers not requiring vascularization.
There are many cancer patients who do not respond to therapy by hormone drugs, and such cancer patients that proliferation of hormone-independent cancer cells is caused by use of hormone drugs, and effects of treatment of cancers by hormone drugs are not continued.
It is desired to develop anticancer agents which are excellent in effects of treating or preventing hormone-independent cancers or their metastasized lesions, or recurred cancers and have no side effects.